This proposal offers a genetic approach to the study of histocompatible tumor resistance with an emphasis on immunological mechanisms. A genetic defect in the ability to mount specific or nonspecific antitumor immunity may render the host susceptible to autochthonous or transplanted histocompatible tumors. The simplest hypothesis to be tested is that there exist H-2 linked immune response genes which control the ability to make an adaptive immune response to tumor specific antigens. Spontaneous tumors may arise and transplanted tumors may flourish in a host which lacks Ir gene(s) specific for that tumor's associated antigen(s). An F1 hybrid with the strain of tumor origin might contribute a new repertoire of dominant Ir genes, including one(s) specific for an important tumor antigen. The phenomenon of superior resistance to histocompatible tumors in F1 hybrids is well documented as the hybrid effect or allogeneic inhibition, and has been shown to be influenced by the H-2 complex. The details of the genetic control of tumor growth and host survival will be examined by comparing differences among various F1 hybrids with the strain of tumor origin as one parent. Opposite parental strains will be chosen in ways which allow independent demonstration of H-2 and non H-2 effects, and congenic mice with recombinant H-2 haplotypes will be used in order to allow more precise H-2 mapping and the ability to recognize possible gene interaction within the major histocompatibility complex. Immunological evaluation of specific and nonspecific antitumor immunity, as each relates to systems shown to be under genetic control, will be directed toward obtaining a more precise understanding of the pathophysiology of host-tumor interactions. This information may help in designing rational tumor therapy approaches which consider the genetic limitations of the host, as well as the characteristics of the tumor. BIBLIOGRAPHIC REFERENCES: Williams, R.M., Leifer, J. and Moore, M.J.: Hybrid effect in natural cell mediated cytotoxicity to SV40 transformed fibroblasts by rat spleen cells. Transplantation, 23:283-286, 1977. Williams, R.M.: Experimental models with possible implications for the role of HLA in malignancy, In: Proceedings of the Symposium on HLA and Malignancy, E. Cohen, ed. Alan R. Liss, Ins., NY, 1977. In press.